Nucleoside transporters in the disposition and targeting of nucleoside analogs in the kidney

Mangravite, Lara M.; Badagnani, Ilaria; Giacomini, Kathleen M.

doi:10.1016/j.ejphar.2003.08.076

Cited by 77 publications

(87 citation statements)

References 73 publications

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“…3A). Since the affinity of ENT1 for cytidine is much higher than for RBV, it was possible that differences in cytidine import were masked by extended incubation periods (36). When cytidine import was examined after 5 min, both RBV R and RBV S Huh7.5 cells again displayed similar levels of cytidine uptake.…”

Section: Rbv R Huh75 Cells With Reduced Rbv Uptakementioning

confidence: 82%

“…Despite the fact that cytidine affinity for ENT1 is 10-fold higher than for ENT2, it was possible that ENT2 or alternate transporters could contribute to cytidine uptake, masking ENT1 transport (36,53). Therefore, cytidine uptake was examined in RBV R and RBV S cells during endogenous equilibrative transport inhibition through NBMPR treatment (Fig.…”

Section: Rbv R Huh75 Cells With Reduced Rbv Uptakementioning

confidence: 99%

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Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

Ibarra

Jain

Pfeiffer

2011

J Virol

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Many individuals infected with hepatitis C virus (HCV) develop a chronic infection, and of those who are treated with pegylated interferon and ribavirin (RBV), many do not respond. While the nucleoside analog RBV improves treatment outcome, and will likely be an important component of therapy with next-generation viral inhibitors, RBV's mechanism is controversial. Most of RBV's proposed mechanisms require RBV import into cells. Therefore, we explored whether host-based RBV resistance develops through reduced cellular uptake, akin to chemotherapy resistance in some cancers. We examined the effect of host-based RBV resistance on HCV replication in cultured hepatoma Huh7.5 liver cells and whether RBV resistance develops in HCV patients. When Huh7.5 cells were exposed to RBV, resistance developed through reduced RBV uptake via the ENT1 nucleoside transporter and antiviral efficacy was reduced. The uptake defect in RBV-resistant cells was specific to RBV, since transport of another ENT1 substrate, cytidine, was unaffected. Importantly, RBV uptake significantly declined in HCV patient peripheral blood mononuclear cells (PBMCs) following 4 weeks of therapy. Furthermore, maintenance of RBV uptake correlated with rapid treatment response. Our results uncovered a novel form of antiviral drug resistance and suggest that host-based RBV resistance develops in HCV patients undergoing therapy and that maintenance of RBV uptake may contribute to rapid viral clearance.

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Section: Rbv R Huh75 Cells With Reduced Rbv Uptakementioning

confidence: 82%

Section: Rbv R Huh75 Cells With Reduced Rbv Uptakementioning

confidence: 99%

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

Ibarra

Jain

Pfeiffer

2011

J Virol

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“…The injected oocytes were stored in modified Barth's medium at 181C for 72 h prior to transport experiments. Groups of seven to nine oocytes were incubated in the presence of Na þ in buffer containing 0.1 mM 3 H-inosine (30 Ci/mmol; Moravek), 3 H-thymidine (61 Ci/ mmol; Moravek), 3 H-adenosine (24 Ci/mmol; Moravek), 3 H-cladribine (17 Ci/mmol; Moravek), or 3 H-fludarabine (6 Ci/mmol; Moravek) and 1 mM of the respective unlabeled substrate at room temperature for 60 min. Uptake was stopped by washing the oocytes five times with ice-cold Na þ free buffer in which Na þ was replaced by choline.…”

Section: Functional Studies Of Slc28a3 Variants In Oocytesmentioning

confidence: 99%

“…Among the cloned human SLC28 transporters, CNT3 is primarily responsible for the transport of several antileukemic drugs, such as cladribine and fludarabine. 2,3 CNT3 has a 2 : 1 Na þ /nucleoside coupling ratio, allowing it to concentrate nucleosides intracellularly 10 times more efficiently than CNT1 or CNT2, which have a 1 : 1 Na þ /nucleoside coupling ratio. 2 Its localization to the apical membrane of the intestine and liver epithelia suggests that CNT3 plays an important role in the absorption and disposition of nucleosides and synthetic nucleoside analogs.…”

Section: Introductionmentioning

confidence: 99%

“…2 Its localization to the apical membrane of the intestine and liver epithelia suggests that CNT3 plays an important role in the absorption and disposition of nucleosides and synthetic nucleoside analogs. 3 A major clinical problem in cancer treatment is intrinsic resistance to the initial drug regimen selected. Although nucleoside analogs (eg, cladribine, fludarabine, and cytarabine) are highly active in lymphoproliferative disorders, a significant portion of patients is resistant to these agents.…”

Section: Introductionmentioning

confidence: 99%

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Functional analysis of genetic variants in the human concentrative nucleoside transporter 3 (CNT3; SLC28A3)

et al. 2005

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The human concentrative nucleoside transporter, CNT3 (SLC28A3), plays an important role in mediating the cellular entry of a broad array of physiological nucleosides and synthetic anticancer nucleoside analog drugs. As a first step toward understanding the genetic basis for interindividual differences in the disposition and response to antileukemic nucleoside analogs, we examined the genetic and functional diversity of CNT3. In all, 56 variable sites in the exons and flanking intronic region of SLC28A3 were identified in a collection of 270 DNA samples from US populations (80 African-Americans, 80 European-Americans, 60 Asian-Americans, and 50 Mexican-Americans). Of the 16 coding region variants, 12 had not been previously reported. Also, 10 resulted in amino-acid changes and three of these had total allele frequencies of Z1%. Nucleotide diversity (p) at nonsynonymous and synonymous sites was estimated to be 1.81 Â 10 4 and 18.13 Â 10 4 , respectively, suggesting that SLC28A3 is under negative selection. All nonsynonymous variants, constructed by site-directed mutagenesis and expressed in Xenopus laevis oocytes, transported purine and pyrimidine model substrates, except for c. 1099G4A (p. Gly367Arg). This rare variant alters an evolutionarily conserved site in the putative substrate recognition domain of CNT3. The presence of three additional evolutionarily conserved glycine residues in the vicinity of p. Gly367Arg that are also conserved in human paralogs suggest that these glycine residues are critical in the function of the concentrative nucleoside transporter family. The genetic analysis and functional characterization of CNT3 variants suggest that this transporter does not tolerate nonsynonymous changes and is important for human fitness.

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Clinical Relevance: Drug–Drug Interactions, Pharmacokinetics, Pharmacodynamics, and Toxicity

et al. 2006

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Nucleoside transporters in the disposition and targeting of nucleoside analogs in the kidney

Cited by 77 publications

References 73 publications

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

Functional analysis of genetic variants in the human concentrative nucleoside transporter 3 (CNT3; SLC28A3)

Clinical Relevance: Drug–Drug Interactions, Pharmacokinetics, Pharmacodynamics, and Toxicity

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